Mechanisms of Coxsackievirus-Induced Damage to Human Pancreatic ß-Cells1
Merja Roivainen,
Suvi Rasilainen,
Petri Ylipaasto,
Riikka Nissinen,
Jarkko Ustinov,
Luc Bouwens,
Décio L. Eizirik,
Tapani Hovi and
Timo Otonkoski2
Enterovirus Laboratory, National Public Health Institute (M.R.,
P.Y., R.N., T.H.), FIN-00300 Helsinki, Transplantation Laboratory,
Haartman Institute (S.R., J.U., T.O.), and Hospital for Children and
Adolescents (T.O.), University of Helsinki, FIN-00014 Helsinki,
Finland; and the Diabetes Research Center, Vrije Universiteit Brussel
(L.B., D.L.E.), B-1090 Brussels, Belgium
Address all correspondence and requests for reprints to: Dr. Merja Roivainen, Enterovirus Laboratory, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail:
merja.roivainen{at}ktl.fi
Enteroviruses may be involved in the pathogenesis of insulin-dependent
diabetesmellitus, either through direct ß-cell infection or as
triggersof autoimmunity. In the present study we investigated the
patternsof infection in adult human islet cell preparations
(consistingof 56 ± 14% ß-cells) by several coxsackieviruses.
Thecells were infected with prototype strains of coxsackievirusB
(CBV) 3, 4, and 5 as well as coxsackievirus A9 (CAV-9). Thepreviously
characterized diabetogenic strain of coxsackievirusB4 (CBV-4-E2) was
used as a reference. All viruses replicatedwell in ß-cells, but only
CBVs caused cell death. Oneweek after infection, the insulin response
of the ß-cellsto glucose or glucose plus theophyline was most
severely impairedby CBV-3 and CBV-5 infections. CBV-4 also caused
significantfunctional impairment, whereas CAV-9-infected cells
respondedlike uninfected controls. After 2 days of infection, about
40%of CBV-5-infected cells had undergone morphological changes
characteristicof pyknosis, i.e. highly distorted nuclei
with condensed butintact chromatin. Both mitochondria and plasma
membrane wereintact in these cells. DNA fragmentation was found in
5.9 ±1.1% of CBV-5-infected ß-cell nuclei (2.1 ± 0.3%
incontrols; P < 0.01). CAV-9 infection did not
induce DNA fragmentation.One week after infection the majority of
infected cells showedcharacteristics of secondary necrosis. Medium
nitrite and induciblenitric oxide synthase messenger ribonucleic acid
levels werenot significantly up-regulated by CBV infection. These
resultssuggest that several enteroviruses may infect human ß-cells.
Theinfection may result in functional impairment or death of the
ß-cellor may have no apparent immediate adverse effects, as shown
herefor CAV-9. Coxsackie B viruses cause functional impairment and
ß-celldeath characterized by nuclear pyknosis. Apoptosis appears to
playa minor role during a productive CBV infection in ß-cells.
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